Distinct roles of the left and right prelimbic cortices in the modulation of ethanol consumption in male mice under acute and chronic social defeat stress.

RATIONALE: Chronic stress exposure disrupts the medial prefrontal cortex's (mPFC) ability to regulate impulses, leading to the loss of control over alcohol drinking in rodents, emphasizing the critical role of this forebrain area in regulating alcohol consumption. Moreover, chronic stress exposure causes lateralization of mPFC functions with volumetric and functional changes, resulting in hyperactivity in the right hemisphere and functional decrease in the left. OBJECTIVES: This study investigated the inhibitory role of the left prelimbic cortex (LPrL) on ethanol consumption induced by chronic social defeat stress (SDS) in male mice and to examine if inactivation of the LPrL causes disinhibition of the right mPFC, leading to an increase in ethanol consumption. We also investigated the role of lateralization and neurochemical alterations in the mPFC related to ethanol consumption induced by chronic SDS. To this end, we examined the activation patterns of ΔFosB, VGLUT2, and GAD67 in the left and right mPFC. RESULTS: Temporarily blocking the LPrL or right PrL (RPrL) cortices during acute SDS did not affect male mice's voluntary ethanol consumption in male mice. When each cortex was blocked in mice previously exposed to chronic SDS, ethanol consumption also remained unaffected. However, male mice with LPrL lesions during chronic SDS showed an increase in voluntary ethanol consumption, which was associated with enhanced ΔFosB/VGLUT2-positive neurons within the RPrL cortex. CONCLUSIONS: The results suggest that the LPrL may play a role in inhibiting ethanol consumption induced by chronic SDS, while the RPrL may be involved in the disinhibition of ethanol consumption.

Cannabidiol modulates chronic neuropathic pain aversion behavior by attenuation of neuroinflammation markers and neuronal activity in the corticolimbic circuit in male Wistar rats.

Chronic neuropathic pain (CNP) is a vast world health problem often associated with the somatosensory domain. This conceptualization is problematic because, unlike most other sensations that are usually affectively neutral and may present emotional, affective, and cognitive impairments. Neuronal circuits that modulate pain can increase or decrease painful sensitivity based on several factors, including context and expectation. The objective of this study was to evaluate whether subchronic treatment with Cannabidiol (CBD; 0.3, 3, and 10 mg/kg intraperitoneal route - i.p., once a day for 3 days) could promote pain-conditioned reversal, in the conditioned place preference (CPP) test, in male Wistar rats submitted to chronic constriction injury (CCI) of the sciatic nerve. Then, we evaluated the expression of astrocytes and microglia in animals treated with CBD through the immunofluorescence technique. Our results demonstrated that CBD promoted the reversal of CPP at 3 and 10 mg/kg. In CCI animals, CBD was able to attenuate the increase in neuronal hyperactivity, measured by FosB protein expression, in the regions of the corticolimbic circuit: anterior cingulate cortex (ACC), complex basolateral amygdala (BLA), granular layer of the dentate gyrus (GrDG), and dorsal hippocampus (DH) - adjacent to subiculum (CA1). CBD also prevented the increased expression of GFAP and IBA-1 in CCI animals. We concluded that CBD effects on CNP are linked to the modulation of the aversive component of pain. These effects decrease chronic neuronal activation and inflammatory markers in regions of the corticolimbic circuit.

Post-weaning social isolation increases the incentive value of nicotine-related contexts and decreases the accumulation of ΔFosB in nucleus accumbens in adolescent rats.

Adolescent social conditions profoundly affect vulnerability to drug abuse. Preclinical studies have shown that preventing social interactions during adolescence increases the rewarding effects of drugs like alcohol, cocaine, or amphetamines, however, little data exist regarding the impact of social isolation on nicotine effects. The current study evaluated the effects of differential rearing conditions during adolescence (isolation or group rearing) on (1) conditioned place preference induced by low nicotine doses (0.1 or 0.3 mg/kg) and (2) sensitization to the locomotor effects of nicotine after sub-chronic administration (3) and accumulation of ΔFosB in nucleus accumbens (NAc). Results showed that nicotine induced place preference in isolated and grouped rats, but the effect was more persistent for the rats reared in isolation. Isolated reared rats also exhibited lower levels of ΔFosB accumulation in NAc. No differences were found in the behavioral sensitization to nicotine effects between rearing conditions. The results suggest that isolation engenders a more robust incentive value of nicotine-related contexts. This effect could be related to the basal expression of ΔFosB: lower levels of this transcription factor seem to impair the motivation of isolated reared rats and increase their vulnerability to the effects of drugs like nicotine.

Prefrontal Cortical Control of Activity in Nucleus Accumbens Core Is Weakened by High-Fat Diet and Prevented by Co-Treatment with N-Acetylcysteine: Implications for the Development of Obesity.

A loss of neuroplastic control on nucleus accumbens (NAc) neuronal activity exerted by the medial prefrontal cortex (mPFC) through long-term depression (LTD) is involved in triggering drug-seeking behavior and relapse on several substances of abuse due to impaired glutamate homeostasis in tripartite synapses of the nucleus accumbens (NAc) core. To test whether this maladaptive neuroplastic mechanism underlies the addiction-like behavior induced in young mice by a high-fat diet (HFD), we utilized 28-days-old male mice fed HFD ad-libitum over 2 weeks, followed by 5 days of HFD abstinence. Control groups were fed a regular diet. HFD fed mice showed increased ΔFosB levels in the NAc core region, whereas LTD triggered from the mPFC became suppressed. Interestingly, LTD suppression was prevented by an i.p. injection of 100 mg/kg N-acetylcysteine 2.5 h before inducing LTD from the mPFC. In addition, excessive weight gain due to HFD feeding was diminished by adding 2mg/mL N-acetylcysteine in drinking water. Those results show a loss of neuroplastic mPFC control over NAc core activity induced by HFD consumption in young subjects. In conclusion, ad libitum consumption of HFD can lead to neuroplastic changes an addiction-like behavior that can be prevented by N-acetylcysteine, helping to decrease the rate of excessive weight gain.

Glutamatergic Neurotransmission Controls the Functional Lateralization of the mPFC in the Modulation of Anxiety Induced by Social Defeat Stress in Male Mice.

The rodent medial prefrontal cortex (mPFC) is anatomically divided into cingulate (Cg1), prelimbic (PrL), and infralimbic (IL) subareas. The left and right mPFC (L and RmPFC) process emotional responses induced by stress-related stimuli, and LmPFC and RmPFC inhibition elicit anxiogenesis and anxiolysis, respectively. Here we sought to investigate (i) the mPFC functional laterality on social avoidance/anxiogenic-like behaviors in male mice subjected to chronic social defeat stress (SDS), (ii) the effects of left prelimbic (PrL) inhibition (with local injection of CoCl2) on the RmPFC glutamatergic neuronal activation pattern (immunofluorescence assay), and (iii) the effects of the dorsal right mPFC (Cg1 + PrL) NMDA receptor blockade (with local injection of AP7) on the anxiety induced by left dorsal mPFC inhibition in mice exposed to the elevated plus maze (EPM). Results showed that chronic SDS induced anxiogenic-like behaviors followed by the rise of ΔFosB labeling and by ΔFosB + CaMKII double-labeling bilaterally in the Cg1 and IL subareas of the mPFC. Chronic SDS also increased ΔFosB and by ΔFosB + CaMKII labeling only on the right PrL. Also, the left PrL inhibition increased cFos + CaMKII labeling in the contralateral PrL and IL. Moreover, anxiogenesis induced by the left PrL inhibition was blocked by NMDA receptor antagonist AP7 injected into the right PrL. These findings suggest the lateralized control of the glutamatergic neurotransmission in the modulation of emotional-like responses in mice subjected to chronic SDS.

Effects of escalating versus fixed ethanol exposure on ∆FosB expression in the mesocorticolimbic pathway in adolescent and adult rats.

Background: We have reported induction of ∆FosB in adolescent rats that drank less ethanol than adults yet exhibited a progressive increase in ethanol intake.Objective: To test the hypothesis that an escalating pattern of ethanol exposure is more effective to induce ∆FosB expression [at prelimbic cortex (PrL), nucleus accumbens core and shell, striatum, basolateral amygdala (BLA) and central amygdala (CeC)] than a pattern equated for number of exposures yet employing a fixed ethanol dose.Methods: Adolescent and adult (Exp. 1, n = 48) male and female (n = 24 of each sex) or only adult male (Exp. 2, n = 36) Wistar rats were intermittently intubated with vehicle, escalating (from 0.5 to 2.5 g/kg) or fixed (2.0 g/kg) doses of ethanol, across 18 sessions. ∆FosB induction was assessed using immunohistochemistry. Ethanol intake, anxiety and risk-taking were assessed (in adults only) via two-bottles tests and the multivariate concentric square field.Results: Both patterns heightened ∆FosB levels similarly in adolescents and adults and in males and females. Fixed dosing induced ∆FosB in all areas (p < .05) except the CeC, whereas the escalating pattern induced ∆FosB in the PrL and BLA only (p < .05). Ethanol intake was initially lower in ethanol pre-exposed subjects than in control subjects (p < .05). Rats exposed to the fixed pattern exhibited enhanced risk-taking behavior (p < .05).Conclusions: The results agree with studies showing ethanol-mediated induction of ∆FosB in reward areas and indicate that, following ethanol intubations, this induction is similar in adolescents and adults. The induction of ∆FosB seems not necessarily associated with susceptibility for ethanol intake.

Repeated crack cocaine administration alters panic-related responses and delta FosB immunoreactivity in panic-modulating brain regions.

Crack cocaine is the crystal form of cocaine, produced by adding sodium bicarbonate to cocaine base paste. Brazil is the largest consumer of crack cocaine in the world. Users of crack cocaine show important physiological and behavioral alterations, including neuropsychiatric symptoms, such as anxiety-related symptoms. Nevertheless, few pre-clinical studies have been previously performed to understand the neurobiological effects of crack cocaine. The purpose of the present study was to investigate effects of the subchronic treatment (5 days, IP) of rats with crack cocaine in an animal model of anxiety/panic, the elevated T-maze (ETM). The ETM model allows the measurement of two behavioral defensive responses, avoidance and escape, in clinical terms, respectively, associated to generalized anxiety and panic disorder, the two main psychiatric conditions that accompany substance use disorders. Immediately after the ETM model, animals were tested in an open field for locomotor activity assessment. Analysis of delta FosB protein immunoreactivity was used to map areas activated by crack cocaine exposure. Results showed that crack treatment selectively altered escape displayed by rats in the ETM test, inducing either a panicolytic (18 mg/kg IP) or a panicogenic-like effect (25 and 36 mg/kg IP). These effects were followed by the altered functioning of panic-modulating brain regions, i.e., the periaqueductal gray and the dorsal region and lateral wings of the dorsal raphe nucleus. Treatment with 36 mg/kg of crack cocaine also increased locomotor activity. These are the first observations performed with crack cocaine in a rodent model of anxiety/panic and contribute to a better understanding of the behavioral and neurobiological effects of crack cocaine.

Anxiogenesis induced by social defeat in male mice: Role of nitric oxide, NMDA, and CRF1 receptors in the medial prefrontal cortex and BNST.

Nitric oxide (NO) release in the right medial prefrontal cortex (RmPFC) produces anxiogenesis. In the bed nucleus of the stria terminalis (BNST), a region that receives neuronal projections from the mPFC, NO provokes anxiety, an effect that is blocked by local injections of corticotrophin-releasing factor type 1 receptor (CRF1) or n-methyl-d-aspartate receptor (NMDAr) antagonist. Anxiety is also enhanced by social defeat stress, and chronic stress impairs and facilitates, respectively, PFC and BNST roles in modulating behavioral responses to aversive situations. This study investigated whether the (i) chronic social defeat stress (CSDS) increases NO signaling in the mPFC; and/or (ii) anxiogenic effects provoked by the intra-RmPFC injection of NOC-9 (an NO donor) or by CSDS are prevented by intra-BNST injections of AP-7 (0.05 nmol) or CP 376395 (3.0 nmol), respectively, NMDAr and CRF1 antagonists, in male Swiss-Webster mice exposed to the elevated plus-maze (EPM). Results showed that (a) CSDS increased anxiety (i.e., reduced open-arm exploration) and repeatedly activated nNOS-containing neurons, as measured by ΔFosB (a stable nonspecific marker of neural activity) + nNOS double-labeling, in the right (but not left) mPFC, (b) NOC-9 in the RmPFC also increased anxiety, and (c) both CSDS and NOC-9 effects were reversed by injections of AP-7 or CP 376395 into the BNST. These results suggest that NMDA and CRF1 receptors located in BNST play an important role in the modulation of anxiety provoked by NO in the RmPFC, as well as by chronic social defeat in mice.

Temporomandibular inflammation mobilizes parvalbumin and FosB/deltaFosB neurons of amygdala and dorsal raphe

Pathophysiological mechanisms involved in orofacial pain and their relationship with emotional disorders have emerged as an important research area for multidisciplinary studies. In particular, temporomandibular disorders (TMD) have been evaluated clinically from both physiological and psychological perspectives. We hypothesized that an altered neuronal activity occurs in the amygdala and the dorsal raphe nucleus (DR), encephalic regions involved in the modulation of painful and emotional information. Adult male Wistar rats were used in an experimental complete Freund's adjuvant (CFA)-induced temporomandibular joint (TMJ) inflammation model. CFA was applied for 1 or 10 days, and the animals were euthanized for brain samples dissection for FosB/ΔFosB and parvalbumin (PV) immunostaining. Our results were consistent in showing that the amygdala and DR were activated in the persistent inflammatory phase (10 days) and that the expression of PV+ interneurons in the amygdala was decreased. In contrast, in the DR, the expression of PV+ interneurons was increased in persistent states of CFA-induced TMJ inflammation. Moreover, at 10 days of inflammation, there was an increased co-localization of PV+ and FosB/ΔFosB+ neurons in the basolateral and central nucleus of the amygdala. Different nuclei of the amygdala, as well as portions of the DR, were activated in the persistent phase (10 days) of TMJ inflammation. In conclusion, altered activity of the amygdala and DR was detected during persistent inflammatory nociception in the temporomandibular joint. These regions may be essential for both sensory and affective dimensions of orofacial pain.

Differential Expression of Striatal ΔFosB mRNA and FosB mRNA After Different Levodopa Treatment Regimens in a Rat Model of Parkinson's Disease.

Levodopa-induced dyskinesia (LID) is the main side effect associated with levodopa treatment and represents the biggest challenge for Parkinson's disease therapy. While the overexpression of ΔFosB transcription factor is related to the development of LID, few studies have been undertaken on fosB gene transcriptional regulation induced by levodopa in vivo. The aim of this study is to evaluate the expression of ΔFosB mRNA and FosB mRNA in the striatum after acute, chronic, and subchronic levodopa treatment in rats with unilateral 6-OHDA-lesion in the medial forebrain bundle. qRT-PCR was used to compare the levels of ΔFosB and FosB mRNA expression in the dopamine-denervated striatum following levodopa treatment. While the results obtained after a single levodopa dose indicate a significant increase of ∆FosB mRNA expression in the striatum 1 h post-injection, the levels returned to baseline values after 24 h. After subchronic levodopa treatment, the levels of ∆FosB and FosB mRNA expression were lower 1 h post-administration of levodopa in comparison with acute effect. However, after chronic levodopa treatment, ∆FosB mRNA expression in the striatum persisted in dyskinetic rats only, and positive correlation was found between the levels of ∆FosB mRNA expression 1 h after levodopa administration and the level of dyskinetic severity. In summary, acute levodopa treatment led to highly increased levels of ∆FosB mRNA expression in the striatum. While repeated administration induced a partial desensitization of the fosB gene in the striatum, it did not suppress its activity completely, which could explain why dyskinesia appears after chronic levodopa treatment.

Circadian disruption favors alcohol consumption and differential ΔFosB accumulation in Corticolimbic structures.

Shift-work and exposure to light at night lead to circadian disruption, which favors the use of alcohol and may be a risk factor for development of addictive behavior. This study evaluated in two experimental models of circadian disruption behavioral indicators of elevated alcohol intake and looked for ΔFosB, which is a transcription factor for neuronal plasticity in corticolimbic structures. Male Wistar rats were exposed to experimental shift-work (AR) or to constant light (LL) and were compared with a control group (LD). After 4 weeks in their corresponding conditions, control LD rats remained rhythmic, AR rats exhibited a loss of day-night patterns in the brain and the LL rats showed arrhythmicity in general activity and day-night PER1 patterns in corticolimbic structures. During 12 days of exposure to 10 percent alcohol solution, the AR group showed daily increased alcohol intake while LD and LL rats ingested similar amounts. After 72 h of alcohol deprivation, AR and LL rats increased alcohol intake in a binge-like test; this could be due not only to circadian disruption but also to stress and/or anxiety developed from the AR and LL manipulations. Associated to the increased alcohol intake, the AR and LL rats had significant accumulation of ΔFosB in the nucleus accumbens shell and decreased ΔFosB in the infralimbic cortex. Data here reported confirm that the disruption of temporal patterns favors the increased alcohol consumption and that this is associated with a differential accumulation of ΔFosB which may favor the development of addictive behavior.

Chronic corticosterone increases ΔFOSB and CRFR1 immunoreactivity in brain regions that modulate aversive conditioning.

Previous studies showed that chronic treatment with corticosterone facilitates elevated T-maze (ETM) inhibitory avoidance and a step-down avoidance task, responses that have been used to investigate aversive conditioning and memory processes. On the other hand, chronic corticosterone does not alter ETM escape from the open arms. The purpose of the present study was to further investigate the effects of chronic corticosterone treatment (200 mg pellets, 21-day release) in an animal model of anxiety that does not involve aversive conditioning: the light/dark transition model. We also investigated the pattern of ΔFosB immunoreactivity (ΔFosB-ir) in different brain regions. To examine how treatment with chronic corticosterone interferes with CRFR1 expression we measured CRFR1 in the same brain structures that exhibited increased ΔFosB-ir. Results showed that chronic treatment with corticosterone did not alter behavioral measurements performed in the light/dark transition model. On the other hand, ΔFosB-ir was increased in several structures that modulate aversive conditioning: the cingulate cortex, the ventro and dorsolateral septum, the amygdala, the paraventricular, dorsomedial and ventromedial hypothalamus, the periaqueductal grey matter, the dorsal raphe, and the median raphe nucleus. Chronic treatment with corticosterone also increased CRFR1-immunoreactivity in the ventrolateral septum, central amygdala, dorsomedial hypothalamus, ventral region of the dorsal raphe and median raphe. These results contribute to a better understanding of the behavioral and neurobiological alterations induced by chronic exposure to glucocorticoids.

FosB mRNA Expression in Peripheral Blood Lymphocytes in Drug Addicted Patients.

FosB gene heterodimerizes with Jun family proteins to form activator protein 1 (AP-1) complexes that bind to AP-1 sites in responsive genes to regulate transcription in all cells. The genic expression of FosB seems to be modified after long time exposure to drugs of abuse and these changes may be involved in craving and addicted behavior. This study investigated the FosB mRNA expression in peripheral blood lymphocytes of drug addicted patients using real-time PCR approach. Thus, patients with crack-cocaine use disorder (CUD, n = 10), alcohol use disorder (AUD, n = 12), and healthy non-addicted subjects (CONT, n = 12) were assessed. FosB mRNA expression was reduced by 1.15-fold in CUD and 2.17-fold in AUD when compared to CONT. Hedge's effect size gs over log FosB/Act was of 0.66 for CUD and of 0.30 for AUD when compared to controls. This study showed that FosB mRNA expression was detected in lymphocytes from peripheral blood for the first time, and it was less expressed in drug addicted patients. This molecular technique may constitute a potential peripheral marker for substance use disorder.

FGF2 Antiproliferative Stimulation Induces Proteomic Dynamic Changes and High Expression of FOSB and JUNB in K-Ras-Driven Mouse Tumor Cells.

Fibroblast growth factor 2 (FGF2) is a well-known cell proliferation promoter; however, it can also induce cell cycle arrest. To gain insight into the molecular mechanisms of this antiproliferative effect, for the first time, the early systemic proteomic differences induced by this growth factor in a K-Ras-driven mouse tumor cell line using a quantitative proteomics approach are investigated. More than 2900 proteins are quantified, indicating that terms associated with metabolism, RNA processing, replication, and transcription are enriched among proteins differentially expressed upon FGF2 stimulation. Proteomic trend dynamics indicate that, for proteins mainly associated with DNA replication and carbohydrate metabolism, an FGF2 stimulus delays their abundance changes, whereas FGF2 stimulation accelerates other metabolic programs. Transcription regulatory network analysis indicates master regulators of FGF2 stimulation, including two critical transcription factors, FOSB and JUNB. Their expression dynamics, both in the Y1 cell line (a murine model of adenocarcinoma cells) and in two other human cell lines (SK-N-MC and UM-UC-3) also susceptible to FGF2 antiproliferative effects, are investigated. Both protein expression levels depend on fibroblast growth factor receptor (FGFR) and src signaling. JUNB and FOSB knockdown do not rescue cells from the growth arrest induced by FGF2; however, FOSB knockdown rescue cells from DNA replication delay, indicating that FOSB expression underlies one of the FGF2 antiproliferative effects, namely, S-phase progression delay.

Environmental enrichment decreases avoidance responses in the elevated T-maze and delta FosB immunoreactivity in anxiety-related brain regions.

Environmental enrichment (EE) is an animal management technique, which seems to improve adaptation to the experimental conditions of housing in laboratory animals. Previous studies have pointed to different beneficial effects of the procedure in the treatment of several disorders, including psychiatric conditions such as depression. The anxiolytic effects induced by EE, on the other hand, are not as clear. In fact, it has been proposed that EE acts as a mild stressor agent. To better understand the relationship of EE with anxiety-related responses, the present study exposed rats to one week of EE and subsequently tested these animals in the inhibitory avoidance and escape tasks of the elevated T-maze (ETM). In clinical terms, these responses have been respectively related to generalized anxiety and panic disorder. All animals were tested in an open field, immediately after the ETM, for locomotor activity assessment. Additionally, analysis of delta FosB protein immunoreactivity (FosB-ir) was used to map areas activated by EE exposure and plasma corticosterone measurements were performed. The results obtained demonstrate that exposure to EE for one week impaired avoidance responses, an anxiolytic-like effect, without altering escape reactions. Also, in animals submitted to the avoidance task EE exposure decreased FosB-ir in the cingulate cortex, dorsolateral and intermediate lateral septum, hippocampus (cornus of Ammon), anterior and dorsomedial hypothalamus, medial and basolateral amygdala and ventral region of the dorsal raphe nucleus. Although no behavioral differences were observed in animals submitted to the escape task, EE exposure also decreased FosB-ir in the cingulate cortex, hippocampus (dentate gyrus), lateral amygdala, paraventricular, anterior and ventromedial hypothalamus, dorsomedial periaqueductal gray and ventral and dorsal region of the dorsal raphe. No changes in corticosterone levels, however, were observed. These results contribute to a better understanding of the effects of EE on anxiety.

FGF2 antiproliferative stimulation induces proteomic dynamic changes and high expression of FOSB and JUNB in K-ras-driven mouse tumor cells

Fibroblast growth factor 2 (FGF2) is a well-known cell proliferation promoter; however, it can also induce cell cycle arrest. To gain insight into the molecular mechanisms of this antiproliferative effect, for the first time, the early systemic proteomic differences induced by this growth factor in a K-Ras-driven mouse tumor cell line using a quantitative proteomics approach are investigated. More than 2900 proteins are quantified, indicating that terms associated with metabolism, RNA processing, replication, and transcription are enriched among proteins differentially expressed upon FGF2 stimulation. Proteomic trend dynamics indicate that, for proteins mainly associated with DNA replication and carbohydrate metabolism, an FGF2 stimulus delays their abundance changes, whereas FGF2 stimulation accelerates other metabolic programs. Transcription regulatory network analysis indicates master regulators of FGF2 stimulation, including two critical transcription factors, FOSB and JUNB. Their expression dynamics, both in the Y1 cell line (a murine model of adenocarcinoma cells) and in two other human cell lines (SK-N-MC and UM-UC-3) also susceptible to FGF2 antiproliferative effects, are investigated. Both protein expression levels depend on fibroblast growth factor receptor (FGFR) and src signaling. JUNB and FOSB knockdown do not rescue cells from the growth arrest induced by FGF2; however, FOSB knockdown rescue cells from DNA replication delay, indicating that FOSB expression underlies one of the FGF2 antiproliferative effects, namely, S-phase progression delay.

Long-term ethanol self-administration induces ΔFosB in male and female adolescent, but not in adult, Wistar rats.

Early-onset ethanol consumption predicts later development of alcohol use disorders. Age-related differences in reactivity to ethanol's effects may underlie this effect. Adolescent rats are more sensitive and less sensitive than adults to the appetitive and aversive behavioral effects of ethanol, respectively, and more sensitive to the neurotoxic effects of experimenter-administered binge doses of ethanol. However, less is known about age-related differences in the neural consequences of self-administered ethanol. ΔFosB is a transcription factor that accumulates after chronic drug exposure and serves as a molecular marker of neural plasticity associated with the transition to addiction. We analyzed the impact of chronic (18 two-bottle choice intake sessions spread across 42days, session length: 18h) ethanol [or only vehicle (control group)] self-administration during adolescence or adulthood on the induction of ΔFosB in several brain areas, anxiety-like behavior, and ethanol-induced locomotor activity and conditioned place preference (CPP) in Wistar rats. Adolescent rats exhibited a progressive escalation of ethanol intake and preference, whereas adult rats exhibited a stable pattern of ingestion. Few behavioral differences in the open field or light-dark test were observed after the intake test. Furthermore, ethanol self-administration did not promote the expression of ethanol-induced CPP. There were, however, large age-related differences in the neural consequences of ethanol drinking: a significantly greater number of ethanol-induced ΔFosB-positive cells was found in adolescents vs. adults in the prelimbic cortex, dorsolateral striatum, nucleus accumbens core and shell, and central amygdala nucleus capsular and basolateral amygdala, with sex-related differences found at central amygdala. This greater ethanol-induced ΔFosB induction may represent yet another age-related difference in the sensitivity to ethanol that may put adolescents at higher risk for problematic ethanol use.

Stress-Induced Locomotor Sensitization to Amphetamine in Adult, but not in Adolescent Rats, Is Associated with Increased Expression of ΔFosB in the Nucleus Accumbens.

While clinical and pre-clinical evidence suggests that adolescence is a risk period for the development of addiction, the underlying neural mechanisms are largely unknown. Stress during adolescence has a huge influence on drug addiction. However, little is known about the mechanisms related to the interaction among stress, adolescence and addiction. Studies point to ΔFosB as a possible target for this phenomenon. In the present study, adolescent and adult rats (postnatal day 28 and 60, respectively) were restrained for 2 h once a day for 7 days. Three days after their last exposure to stress, the animals were challenged with saline or amphetamine (1.0 mg/kg i.p.) and amphetamine-induced locomotion was recorded. Immediately after the behavioral tests, rats were decapitated and the nucleus accumbens was dissected to measure ΔFosB protein levels. We found that repeated restraint stress increased amphetamine-induced locomotion in both the adult and adolescent rats. Furthermore, in adult rats, stress-induced locomotor sensitization was associated with increased expression of ΔFosB in the nucleus accumbens. Our data suggest that ΔFosB may be involved in some of the neuronal plasticity changes associated with stress induced-cross sensitization with amphetamine in adult rats.

Effects and molecular mechanism of chitosan-coated levodopa nanoliposomes on behavior of dyskinesia rats.

BACKGROUND: Chitosan, the N-deacetylated derivative of chitin, is a cationic polyelectrolyte due to the presence of amino groups, one of the few occurring in nature. The use of chitosan in protein and drug delivery systems is being actively researched and reported in the literature. RESULTS: In this study, we used chitosan-coated levodopa liposomes to investigate the behavioral character and the expression of phosphorylated extracellular signal-regulated kinase (ERK1/2), dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and FosB/ΔFosB in striatum of rat model of levodopa-induced dyskinesia (LID). We found that scores of abnormal involuntary movement (AIM) decreased significantly in liposome group (P < 0.05), compared with levodopa group. Levels of phospho-ERK1/2, phospho-Thr34 DARPP-32 and FosB/ΔFosB in striatum decreased significantly in liposome group lesion side compared with levodopa group (P < 0.05). However, both of two groups above have significantly differences compared with the control group (P < 0.05). CONCLUSION: Chitosan-coated levodopa liposomes may be useful in reducing dyskinesias inducing for Parkinson disease. The mechanism might be involved the pathway of signaling molecular phospho-ERK1/2, phospho-Thr34 DARPP-32 and ΔFosB in striatum.